The induction of heme oxygenase-1 suppresses heat shock protein 90 and the proliferation of human breast cancer cells through its byproduct carbon monoxide

Lee, Wen Ying; Chen, Yen-Chou; Shih, Chwen‐Ming; Lin, Chun-Mao; Cheng, Chia‐Hsiung; Chen, Ku‐Chung; Lin, Chun-Yu

doi:10.1016/j.taap.2013.10.027

Cited by 55 publications

(43 citation statements)

References 50 publications

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“…As described in the literature, LPS in vitro stimulation triggers increased HO-1 expression, induced by IL-10, via a p38 MAPK-dependent pathway (Lee and Chau, 2002). In addition, it has been demonstrated that carbon monoxide attenuates Hsp90 activity and promotes dissociation of its client proteins (Lee et al, 2014). Here, we demonstrate that this stressinducible protein was increased by gedunin incubation in the presence or absence of LPS, suggesting that, in our experimental model, gedunin effects are likely a result of both MD-2 binding and Hsp90 modulation.…”

Section: Discussionmentioning

confidence: 80%

Gedunin Binds to Myeloid Differentiation Protein 2 and Impairs Lipopolysaccharide-Induced Toll-Like Receptor 4 Signaling in Macrophages

et al. 2015

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Recognition of bacterial lipopolysaccharide (LPS) by innate immune system is mediated by the cluster of differentiation 14/ Toll-like receptor 4/myeloid differentiation protein 2 (MD-2) complex. In this study, we investigated the modulatory effect of gedunin, a limonoid from species of the Meliaceae family described as a heat shock protein Hsp90 inhibitor, on LPS-induced response in immortalized murine macrophages. The pretreatment of wild-type (WT) macrophages with gedunin (0.01-100 mM, noncytotoxic concentrations) inhibited LPS (50 ng/ml)-induced calcium influx, tumor necrosis factor-a, and nitric oxide production in a concentration-dependent manner. The selective effect of gedunin on MyD88-adapter-like/myeloid differentiation primary response 88-and TRIF-related adaptor molecule/TIR domain-containing adapter-inducing interferon-b-dependent signaling pathways was further investigated. The pretreatment of WT, TIR domain-containing adapter-inducing interferon-b knockout, and MyD88 adapter-like knockout macrophages with gedunin (10 mM) significantly inhibited LPS (50 ng/ml)-induced tumor necrosis factor-a and interleukin-6 production, at 6 hours and 24 hours, suggesting that gedunin modulates a common event between both signaling pathways. Furthermore, gedunin (10 mM) inhibited LPS-induced prostaglandin E 2 production, cyclooxygenase-2 expression, and nuclear factor kB translocation into the nucleus of WT macrophages, demonstrating a wide-range effect of this chemical compound. In addition to the ability to inhibit LPS-induced proinflammatory mediators, gedunin also triggered anti-inflammatory factors interleukin-10, heme oxygenase-1, and Hsp70 in macrophages stimulated or not with LPS. In silico modeling studies revealed that gedunin efficiently docked into the MD-2 LPS binding site, a phenomenon further confirmed by surface plasmon resonance. Our results reveal that, in addition to Hsp90 modulation, gedunin acts as a competitive inhibitor of LPS, blocking the formation of the Toll-like receptor 4/MD-2/LPS complex.

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Section: Discussionmentioning

confidence: 80%

Gedunin Binds to Myeloid Differentiation Protein 2 and Impairs Lipopolysaccharide-Induced Toll-Like Receptor 4 Signaling in Macrophages

et al. 2015

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“…Interestingly, an accelerating cycle has been observed, as the CO released from CORM induced HO-1 expression which further promoted CO production. Interestingly, although all products of HO-1 can affect cell growth, only CO was able to suppress HSP90 [96].…”

Section: Breast Cancermentioning

confidence: 98%

“…Importantly, CO blocked the growth of breast cancer cells independently of p53. In MCF7 cells expressing WT p53 protein CO treatment upregulated its expression while in MDA-MB-231 cells, which express mutated form, the p53 protein was destabilized, ubiquitinated and degraded by in response to CO [96]. Interestingly, an accelerating cycle has been observed, as the CO released from CORM induced HO-1 expression which further promoted CO production.…”

Section: Breast Cancermentioning

confidence: 99%

“…The effect might be mediated by CO, which inhibited ERK/AP-1 activation (cytacja). Recent study by Lee et al [96] showed that in breast cancer MCF7 and MDA-MB-231 cells CO inhibited the HSP90 client protein activity, such as AKT, ERα, and cyclin D1. Exogenously applied CO (treatment with a CO-releasing compound, CORM-2) downregulated also the expression of cyclin D1, CDK4 and hTERT.…”

Section: Breast Cancermentioning

confidence: 99%

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HO-1/CO system in tumor growth, angiogenesis and metabolism — Targeting HO-1 as an anti-tumor therapy

Łoboda

Józkowicz

Dulak

2015

Vascular Pharmacology

158

155

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“…For example, in lipopolysaccharide-activated murine macrophage RAW264.7 cells, CoPP suppresses phosphorylation of JNK, but not ERK, whereas CoPP alone has no effect on both phosphorylation of ERK and JNK in unstimulated cells (Lin et al, 2009). In rat heart or human colon cancer CaCo2 cells (Busserolles et al, 2006), CoPP induces phosphorylation of Akt, whereas in human breast cancer cells it reduces phosphorylation of Akt (Lee et al, 2014). Thus, CoPP has unique inhibitory effects on RANKL-stimulation OCL differentiation through blocking multiple signaling pathways in OCLs.…”

Section: Discussionmentioning

confidence: 99%

Cobalt protoporphyrin represses osteoclastogenesis through blocking multiple signaling pathways

et al. 2015

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Abstract.Cobalt protoporphyrin (CoPP) is a metallo-protoporphyrin that works as a powerful inducer of heme oxigenase-1 (HO-1) in various tissues and cells. Our recent studies have demonstrated that induction of HO-1 by several reagents inhibited differentiation and activation of osteoclasts (OCLs), which are multinucleated bone resorbing cells. However, the effects of CoPP on osteoclastogenesis remain to be elucidated. In this study, we report that CoPP inhibits receptor activator of nuclear factor κB ligand (RANKL)-induced OCL formation in a dose dependent manner. Importantly, CoPP had little cytotoxicity, but rather enhanced cell proliferation of OCLs. CoPP suppressed the protein levels of nuclear factor of activated T cells cytoplasmic-1 (NFATc1) as well as those of OCLs markers such as Src and cathepsin K, which are transcriptionally regulated by NFATc1 in mature OCLs. Western blot analyses also showed that CoPP abolished RANKL-stimulated phosphorylation of several major signaling pathways such as IκB, Akt, ERK, JNK and p38 MAPKs in OCL precursor cells. Thus, our results show that CoPP represses osteoclastogenesis through blocking multiple signaling pathways.

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The induction of heme oxygenase-1 suppresses heat shock protein 90 and the proliferation of human breast cancer cells through its byproduct carbon monoxide

Cited by 55 publications

References 50 publications

Gedunin Binds to Myeloid Differentiation Protein 2 and Impairs Lipopolysaccharide-Induced Toll-Like Receptor 4 Signaling in Macrophages

Gedunin Binds to Myeloid Differentiation Protein 2 and Impairs Lipopolysaccharide-Induced Toll-Like Receptor 4 Signaling in Macrophages

HO-1/CO system in tumor growth, angiogenesis and metabolism — Targeting HO-1 as an anti-tumor therapy

Cobalt protoporphyrin represses osteoclastogenesis through blocking multiple signaling pathways

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